Early Permissiveness of Central Nervous System Cells to Measles Virus Infection Is Determined by Hyperfusogenicity and Interferon Pressure.

The cessation of measles virus (MeV) vaccination in more than 40 countries as a consequence of the COVID-19 pandemic is expected to significantly increase deaths due to measles. MeV can infect the central nervous system (CNS) and lead to lethal encephalitis. Substantial part of virus sequences recovered from patients' brain were mutated in the matrix and/or the fusion protein (F). Mutations of the heptad repeat domain located in the C terminal (HRC) part of the F protein were often observed and were associated to hyperfusogenicity. These mutations promote brain invasion as a hallmark of neuroadaptation. Wild-type F allows entry into the brain, followed by limited spreading compared with the massive invasion observed for hyperfusogenic MeV. Taking advantage of our ex vivo models of hamster organotypic brain cultures, we investigated how the hyperfusogenic mutations in the F HRC domain modulate virus distribution in CNS cells. In this study, we also identified the dependence of neural cells susceptibility on both their activation state and destabilization of the virus F protein. Type I interferon (IFN-I) impaired mainly astrocytes and microglial cells permissiveness contrarily to neurons, opening a new way of consideration on the development of treatments against viral encephalitis.

Infection, pathology and interferon treatment of the SARS-CoV-2 Omicron BA.1 variant in juvenile, adult and aged Syrian hamsters.

The new predominant circulating SARS-CoV-2 variant, Omicron, can robustly escape current vaccines and neutralizing antibodies. Although Omicron has been reported to have milder replication and disease manifestations than some earlier variants, its pathogenicity in different age groups has not been well elucidated. Here, we report that the SARS-CoV-2 Omicron BA.1 sublineage causes elevated infection and lung pathogenesis in juvenile and aged hamsters, with more body weight loss, respiratory tract viral burden, and lung injury in these hamsters than in adult hamsters. Juvenile hamsters show a reduced interferon response against Omicron BA.1 infection, whereas aged hamsters show excessive proinflammatory cytokine expression, delayed viral clearance, and aggravated lung injury. Early inhaled IFN-α2b treatment suppresses Omicron BA.1 infection and lung pathogenesis in juvenile and adult hamsters. Overall, the data suggest that the diverse patterns of the innate immune response affect the disease outcomes of Omicron BA.1 infection in different age groups.

Biologics in COVID-19 So Far: Systematic Review.

This systematic review aimed to reevaluate the available evidence of the use of biologics as treatment candidates for the treatment of severe and advanced COVID-19 disease; what are the rationale for their use, which are the most studied, and what kind of efficacy measures are described? A search through Cochrane, Embase, Pubmed, Medline, medrxiv.org, and Google scholar was performed on the use of biologic interventions in COVID-19/SARS-CoV-2 infection, viral pneumonia, and sepsis, until 11 January 2022. Throughout the research, we identified 4821 records, of which 90 were selected for qualitative analysis. Amongst the results, we identified five popular targets of use: IL6 and IL1 inhibitors, interferons, mesenchymal stem cells treatment, and anti-spike antibodies. None of them offered conclusive evidence of their efficacy with consistency and statistical significance except for some studies with anti-spike antibodies; however, Il6 and IL1 inhibitors as well as interferons show encouraging data in terms of increased survival and favorable clinical course that require further studies with better methodology standardization.

The Effect of IFN-ß Treatment on Plasma Levels of BDNF and IL-6 in Relapsing-Remitting Multiple Sclerosis Patients.

BACKGROUND: In recent investigations addressing neurodegenerative diseases, especially multiple sclerosis (MS), the roles of brain-derived neurotrophic factor (BDNF) and interleukin-6 (IL-6) have been examined. METHODS: Forty-five relapsing-remitting MS (RRMS) patients, including 32 IFN-ß-treated and 13 newly identified untreated cases as well as 45 sex- and age-matched healthy controls, were recruited in the study. Plasma levels of BDNF and IL-6 were assessed using the ELISA method. Data were analyzed by SPSS (ver.21). RESULTS: There were significant differences between the case and healthy control groups in terms of the plasma levels of BDNF (p value = 0.044) and IL-6 (p value <0.001). Besides, the treatment with IFN-ß had no significant impact on the level of BDNF or IL-6 in RRMS patients as compared to healthy controls (p value = 0.716 and 0.623 for BDNF and IL-6, respectively). Furthermore, the increase in the plasma levels of BDNF and IL-6 indicated a direct correlation in the case group (r = 0.508, p value = 0.008). In detail, following the classification of the case group into 2 subgroups of IFN-ß-treated and untreated patients, a direct positive correlation was observed between the plasma levels of BDNF and IL-6 in IFN-ß-treated patients (r = 0.495, p value = 0.026). CONCLUSION: The IFN-ß treatment seems not to be effective for upregulating BDNF and IL-6 in RRMS patients.

Type I interferon gene expression in antiphospholipid syndrome: Pathogenetic, clinical and therapeutic implications.

Type I Interferon gene expression has been shown to play an important role in the pathogenesis of several systemic autoimmune disorders, paving the way for its potential use as a surrogate marker or a therapeutic tool. While the concept of type I interferon signature and its correlation with clinical phenotypes and disease activity, along with anti-interferon targeted therapy have been vastly investigated in patients with systemic lupus erythematosus, there is a paucity of data concerning antiphospholipid syndrome patients. In this review, we summarize the current knowledge on the pathogenetic and clinical implications of type I interferon expression in antiphospholipid syndrome and discuss the therapeutic possibility of targeting molecules along the interferon signaling pathway. A number of recent studies have shown a type I interferon gene expression induction in patients with primary antiphospholipid syndrome via the plasmacytoid dendritic cell pathway, toll like receptors (TLRs) such as TLR7 and TLR9, anti-beta2glycoprotein I antibody-mediated neutrophil activation and neutrophil extracellular traps (NETs) release in a TLR4-dependent fashion, and a subsequent B cell and plasmablast activation. An association between type I interferon expression and several demographic, clinical and laboratory characteristics including age, gender, pregnancy complications such as eclampsia, anti-beta2glycoprotein I antibodies, and a negative correlation with hydroxychloroquine and/or statin use, has been shown. Correlation of high interferon scores to worse outcomes in prospective studies could direct the initiation for a prompt treatment in high-risk populations. Potential therapeutic approaches targeting type I interferon production and signaling pathway components might include anti-interferon or interferon receptor monoclonal antibodies, or an interferon based therapeutic vaccine as was indicated from previous systemic lupus erythematosus studies, TLR inhibitors including hydroxychloroquine and anti-TLR antibodies, plasmacytoid dendritic cell inhibition, adenosine-receptor agonists, and plasmablast targeting treatments. Well-designed studies are needed to further assess the immunomodulatory potential of the above targets for therapeutic intervention in patients with primary antiphospholipid syndrome.

Rapid and persistent decline in soluble CD163 with successful direct-acting antiviral therapy and associations with chronic hepatitis C histology.

BACKGROUND AND AIM: Soluble CD 163 (sCD163) is released from activated liver macrophages in chronic viral hepatitis C (HCV) and serum levels reflect liver disease severity. The impact of direct-acting antiviral (DAA)-therapy on sCD163-levels and the ability of sCD163 to predict the presence of liver fibrosis remain unclear. In a combined observational and prospective study, we aimed to investigate changes in sCD163 with DAA-treatment, to investigate associations between sCD163 and histopathological activity and fibrosis and to validate the sCD163-based fibrosis score in HCV-patients. METHODS: We examined three groups of patients: an Australian (n = 28) treated with pegylated-interferon and a first-generation DAA, a Danish (n = 38) treated with sofosbuvir-based DAA-regimens and a Japanese (n = 562) assessed for activity and fibrosis (Metavir scoring system) in liver biopsies. Serum sCD163-levels were quantified by ELISA. RESULTS: Thirteen (46%) of the Australian patients achieved sustained virological response (SVR) and only these patients had significant decreases in sCD163-levels (2.7 (95%CI:1.9-3.6) vs. 4.1(2.9-5.7) mg L - 1, p = .008). In the Danish group, 37 (97%) patients achieved SVR at 12-weeks post-treatment with 32% reduction in sCD163-levels (5.0 (4.3-5.8) vs. 7.4 (6.3-8.7), p < .001). The decline was rapid and persisted 12 months after treatment cessation (p < .007). sCD163 levels increased in parallel with inflammatory activity and fibrosis (p < .001). The sCD163-based fibrosis score outperformed established fibrosis scores for significant fibrosis (areas under the receiver operating characteristics curves (AUROCs): 0.79 (0.75-0.83) vs. aspartate aminotransferase to platelet ratio index (APRI) 0.73 (0.69-0.77), Fibrosis-4 (FIB-4) 0.74 (0.70-0.78), p < .001). CONCLUSION: sCD163-levels decline rapidly with successful DAA therapy and are associated with histological inflammatory activity and fibrosis, confirming a key role for macrophages in HCV inflammation and fibrosis and supporting sCD163 as a biomarker of treatment response.

Alterations in the metabolism of tryptophan in patients with chronic hepatitis C six months after pegylated interferon-α 2a treatment.

BACKGROUND: Risk of depression and suicide in patients on interferon remains also after the treatment, the pathogenesis of which is still unclear. We aimed to determine the influence of the PEG-IFN-α2a on tryptophan metabolism along the kynurenine pathway during treatment and up to 6 months after the end of treatment. METHODS: We evaluated 101 patients with chronic hepatitis C treated with PEG-IFN-α2a, and 40 controls, so as to determine the activation of indolamine 2,3-dioxygenase (IDO) and tryptophan (TRP) and their metabolites' concentrations/levels: kynurenine (KYN), kynurenic acid (KYNA) and anthranilic acid (AA). The subjects were evaluated before and after weeks 2, 4, 8, 12, 24, 48, as well as 6 months after the end of the treatment. RESULTS: In the group of patients treated 24 weeks, six months after the end of treatment IDO activity was significantly higher compared to baseline (69.5 vs 57.2 ß = 0.21 P = 0.000); TRP concentration was significantly lower compared to baseline (30.0 vs 35.6 ß=-0.21 P = 0.001); KYNA concentration was significantly higher compared to baseline (37.2 nmol/L vs 29.4 nmol/L ß = 0.22 P = 0.02), and AA concentration was significantly higher compered to baseline (51.0 nmol/L vs 38.4 nmol/L ß = 0.22 P = 0.05) In the group of patients treated 48 weeks six months, after the end of treatment both the IDO activity and KYNA concentration were significantly higher compared to baseline (respective values - IDO: 78.8 vs 56.2 ß = 0.14 P = 0.02; KYNA: 39.2 nmol/L vs 27.0 nmol/L ß = 0.26 P = 0.000). CONCLUSIONS: This is the first report of a prolonged activation of IDO six months after the end of PEG-IFN-α2a treatment. The clinical significance of the finding can be implicated in the pathophysiology of depressive episodes.

Hepatitis D virus replication is sensed by MDA5 and induces IFN-ß/λ responses in hepatocytes.

BACKGROUND & AIMS: Hepatitis B virus (HBV) and D virus (HDV) co-infections cause the most severe form of viral hepatitis. HDV induces an innate immune response, but it is unknown how the host cell senses HDV and if this defense affects HDV replication. We aim to characterize interferon (IFN) activation by HDV, identify the responsible sensor and evaluate the effect of IFN on HDV replication. METHODS: HDV and HBV susceptible hepatoma cell lines and primary human hepatocytes (PHH) were used for infection studies. Viral markers and cellular gene expression were analyzed at different time points after infection. Pattern recognition receptors (PRRs) required for HDV-mediated IFN activation and the impact on HDV replication were studied using stable knock-down or overexpression of the PRRs. RESULTS: Microarray analysis revealed that HDV but not HBV infection activated a broad range of interferon stimulated genes (ISGs) in HepG2NTCP cells. HDV strongly activated IFN-ß and IFN-λ in cell lines and PHH. HDV induced IFN levels remained unaltered upon RIG-I (DDX58) or TLR3 knock-down, but were almost completely abolished upon MDA5 (IFIH1) depletion. Conversely, overexpression of MDA5 but not RIG-I and TLR3 in HuH7.5NTCP cells partially restored ISG induction. During long-term infection, IFN levels gradually diminished in both HepG2NTCP and HepaRGNTCP cell lines. MDA5 depletion had little effect on HDV replication despite dampening HDV-induced IFN response. Moreover, treatment with type I or type III IFNs did not abolish HDV replication. CONCLUSION: Active replication of HDV induces an IFN-ß/λ response, which is predominantly mediated by MDA5. This IFN response and exogenous IFN treatment have only a moderate effect on HDV replication in vitro indicating the adaption of HDV replication to an IFN-activated state. LAY SUMMARY: In contrast to hepatitis B virus, infection with hepatitis D virus induces a strong IFN-ß/λ response in innate immune competent cell lines. MDA5 is the key sensor for the recognition of hepatitis D virus replicative intermediates. An IFN-activated state did not prevent hepatitis D virus replication in vitro, indicating that hepatitis D virus is resistant to self-induced innate immune responses and therapeutic IFN treatment.

Brain Volume Loss During the First Year of Interferon-Beta Treatment in Multiple Sclerosis: Baseline Inflammation and Regional Brain Volume Dynamics.

OBJECTIVE: A pseudoatrophy effect, mostly affecting white matter, can be observed in patients with multiple sclerosis (MS) early on natalizumab therapy. We aimed to investigate whether a similar pattern could be found after interferon-beta treatment onset. METHODS: From a prospective, ongoing cohort, 123 patients treated with interferon-beta were included. A brain MRI was performed at baseline (3 months prior) and 12 months after therapy onset in all patients. SPM8 software was used for volumetric analysis. Brain parenchymal, gray and white matter volumes at baseline and follow-up were obtained, allowing calculation of percentage of volume changes (BVc, GMVc, and WMVc, respectively). Descriptive statistics and linear regression models were performed. RESULTS: Eighty-four patients were analyzed (39 patients were excluded mostly due to incomplete MRI protocol or segmentation errors); baseline mean age was 33.6 years (SD 8.7), median disease duration was 2.8 years (.3-14), and median EDSS was 1.5 (0-6). Forty-nine patients (58.3%) had baseline gadolinium-enhancing (Gd+) lesions with a median number of 1 (0-18). The regression analysis (adjusted by the number of Gd+ at follow-up MRI, age, disease duration, and baseline EDSS) showed that a higher baseline number of Gd+ lesions was predictive of larger decreases in BVc and WMVc (P = .013 and P = .003, respectively) but not GMVc (P = .777). CONCLUSION: Concurrent inflammation has an impact on brain volume measurements (especially white matter) during the first year of interferon-beta therapy, and should be taken into account when interpreting early brain volume changes on therapy.

Association Between Level of Hepatitis D Virus RNA at Week 24 of Pegylated Interferon Therapy and Outcome.

BACKGROUND & AIMS: Interferon is the only effective treatment for chronic hepatitis D virus (HDV) infection. No rules have been set for stopping treatment based on viral kinetics. We analyzed data from an international study of hepatitis D treatment to identify factors associated with outcomes of pegylated interferon treatment, with and without adefovir. METHODS: We analyzed data from the Hep-Net-International Delta Hepatitis Intervention Trial on 50 patients with compensated liver disease who tested positive for anti-HDV and HDV RNA. Subjects received pegylated interferon α 2a, with adefovir or placebo, or only adefovir, for 48 weeks. Twenty-four weeks after treatment ended, 41 patients were evaluated for levels of HDV RNA and DNA, liver enzymes, and hepatitis B surface antigen (HBsAg); liver biopsy specimens were analyzed for fibrosis. Response to therapy was defined as end-of-treatment response or post-treatment week 24 virologic response. In both cases virologic response was associated with undetectable HDV RNA levels. Patients with less than a 1 log decrease in HDV RNA at the end of treatment were considered null responders. RESULTS: Based on univariate and multivariate analysis, the level of HDV RNA at week 24 of treatment was associated more strongly with response to therapy than other factors analyzed. The level of HBsAg at week 24 of treatment was associated with a response to therapy only in univariate analysis. Lack of HDV RNA at week 24 of treatment, or end of treatment, identified responders with positive predicted values of 71% and 100%, respectively. At 24 weeks after treatment, a decrease in HDV RNA level of less than 1 log, combined with no decrease in HBsAg level, identified null responders with a positive predictive value of 83%. A decrease in HDV RNA level of more than 2 log at week 24 of treatment identified null responders with a negative predictive value of 95%. CONCLUSIONS: Based on an analysis of data from a large clinical trial, the level of HDV RNA at week 24 of treatment with pegylated interferon, with or without adefovir for 48 weeks, can identify patients who will test negative for HDV RNA 24 weeks after the end of treatment. This information can be used to help physicians manage patients receiving therapy for chronic hepatitis D.

Vitamin D status and effect of interferon-ß1a treatment on MRI activity and serum inflammation markers in relapsing-remitting multiple sclerosis.

To explore if vitamin D modulates interferon-ß1a treatment effects in relapsing-remitting multiple sclerosis, we examined relationships between serum vitamin D and magnetic resonance imaging (MRI) activity and ten systemic inflammation markers in 88 patients, before and during treatment. Odds ratios for all MRI parameters were negatively associated with vitamin D levels before therapy, but converged to equally low values irrespective of vitamin D status during treatment. During therapy, similar alterations of MRI activity and inflammation markers were found across patients categorized by mean vitamin D values. This suggests that vitamin D status has no major influence on interferon-ß1a treatment effects.

High incidence of the hepatitis C virus recombinant 2k/1b in Georgia: Recommendations for testing and treatment.

AIM: The first hepatitis C virus (HCV) recombinant, RF2k/1b, was initially described from Russia and has since then been identified from patients in Ireland, Estonia, Uzbekistan and Cyprus. Many of these patients originated from Georgia; however, there is no information on its prevalence in Georgia or its susceptibility to antiviral treatment. METHODS: We retrospectively sequenced the non-structural region 5B (NS5B) of the HCV genome in samples from 72 Georgian patients, 36 of whom had been treated with pegylated interferon and ribavirin. RESULTS: The HCV genotype was determined using the Versant HCV Genotype v2 kit. Based on this typing, 32 patients (44.4%) were infected with genotype 1, 21 (29.1%) genotype 2 and 19 (26.3%) genotype 3. Partial NS5B of these strains was sequenced and analyzed for type, with concordant genotype results for all type 1 and 3 strains. Discrepant results were observed for genotyped 2 strains, with 16 (76%) having NS5B of subtype 1b. On phylogenetic analysis, 15 NS5B sequences of these strains were found in a clade formed by recombinant RF2k/1b strains. The remaining discordant sequence was found within a clade formed by 1b strains. CONCLUSION: Our findings show that the RF2k/1b recombinant strain is common among Georgian patients previously assumed to be infected with genotype 2. Because genotyping is mainly performed to decide treatment strategies, there is a need to determine the genotype by analysis of at least two genomic regions in strains from Georgian patients considered infected with genotype 2 based on standard HCV genotyping methods.

IFNL4 polymorphism predicts response to hepatitis C treatment after liver transplantation.

BACKGROUND: Recent studies in chronic hepatitis C patients have shown that rs368234815 polymorphism nearby IL28B is a better predictor of response to antiviral treatment with pegylated interferon and ribavirin than IL28B polymorphisms (rs12979860 and rs8099917). Its effect could be related to interferon lambda 4 (IFNL4), a protein which seems to confer some paradoxical disadvantages in hepatitis C virus (HCV) immune response. OBJECTIVES: To assess the role of IFNL4 rs368234815 polymorphism on the response to antiviral treatment after liver transplantation (LT). STUDY DESIGN: IFNL4 and IL28B polymorphisms were genotyped in 86 HCV-infected LT recipients and in their donors; all patients had undergone antiviral treatment with pegylated interferon and ribavirin after LT. RESULTS: IFNL4 polymorphism strongly correlated with IL28B ones (p < 0.001). The favorable IFNL4 genotype (TT/TT) was significantly more frequent among donors than recipients (60% donors vs. 22% recipients, p <0.001). Recipient TT/TT genotype was associated with a higher sustained virological response rate after LT (p = 0.024). Nevertheless, the highest sustained virological response frequency was found when both donors and recipients had favorable genotypes (73% vs. 25%, p = 0.002), suggesting a role for donor genotype. CONCLUSIONS: Our study demonstrates that IFNL4 rs368234815 polymorphism is an important predictor of response to antiviral treatment in the LT setting. These findings warrant further studies on IFNL4 role in immune response against HCV.

Serum levels of IL-17A in patients with relapsing-remitting multiple sclerosis treated with interferon-ß.

BACKGROUND: Interleukin-17 (IL-17), which is secreted by Th17 cells, is a proinflammatory cytokine that is implicated in the pathogenesis of multiple sclerosis (MS) and plays a role in nonresponse of MS patients to interferon-ß (IFN-ß) therapy. OBJECTIVES: The purpose of this study was to establish a correlation between nonresponders (NR) and IL-17A serum titers and binding antibodies (BAbs) to IFN-ß, as well as to find a correlation between IL-17A serum levels and other features of MS patients. METHODS: Our prospective study included 72 inactive relapsing-remitting multiple sclerosis (RRMS) patients that had been treated for at least 18 months with IFN-ß and 15 healthy subjects. We determined the serum levels of IL-17A and of BAbs. IL-17A levels were considered elevated (IL-17A+) if the recorded value was greater than 1.6 pg/ml. RESULTS: Twenty-seven patients (37.5%) were NR and had a significantly higher serum IL-17A level compared to the responders group. Nineteen patients (26.4%) were IL-17A+ and had had a significantly higher number of relapses in the previous year and a higher Expanded Disability Status Score. The majority of IL-17A+ patients were NR and had a shorter MS duration. CONCLUSIONS: RRMS patients with high serum IL-17A levels do not respond well to IFN-ß therapy and have shorter MS duration compared to patients with low IL-17A levels. This response is not influenced by the presence of BAbs.

The diagnosis and management of giant cell lesions of the jaws.

This article will review current thoughts with regard to the etiology, histopathology, diagnosis, and management of giant cell lesions of the jaws. It will attempt to point out the differences between these lesions and giant cell lesions elsewhere in the body and also the current techniques for medical management of these conditions including steroid injections, calcitonin treatment, and alpha interferon treatment.

Distribution of the human leukocyte antigen class II alleles in Brazilian patients with chronic hepatitis C virus infection

Hepatitis C virus (HCV) infection is a global medical problem. The current standard of treatment consists of the combination of peginterferon plus ribavirin. This regimen eradicates HCV in 55 percent of cases. The immune response to HCV is an important determinant of disease evolution and can be influenced by various host factors. HLA class II may play an important role in immune response against HCV. The objective of the present study was to determine the distribution of HLA class II (DRB1 and DQB1) alleles, their association with chronic HCV infection and their response to interferon therapy. One hundred and two unrelated white Brazilian patients with chronic HCV infection, 52 responders (45 males and 7 females) and 50 non-responders (43 males and 7 females) to antiviral treatment, were included in the study. Healthy Brazilian bone marrow donors of Caucasian origin from the same geographic area constituted the control group (HLA-DRB1, N = 99 and HLA-DQB1, N = 222 individuals). HLA class II genotyping was performed using a low-resolution DRB1, DQB1 sequence-specific primer amplification. There were higher frequencies of HLA-DRB1*13 (26.5 vs 14.1 percent) and HLA-DQB1*02 (52.9 vs 38.7 percent) in patients compared with controls; however, these were not significantly different after P correction (Pc = 0.39 and Pc = 0.082, respectively). There was no significant difference between the phenotypic frequencies of HLA-DRB1 (17.3 vs 14.0 percent) and HLA-DQB1 alleles in responder and non-responder HCV patients. The HLA-DRB1*07 allele was significantly more common in HCV patients (33.3 vs 12.1 percent) than in controls (Pc = 0.0039), suggesting that the HLA-DRB1*07 allele is associated with chronic HCV infection.

Bronchial Carcinoid Tumor treated with Interferon and a new vaccine against NeuGcGM3 Antigen Expressed in malignant carcinoid cells

A case of a 16-year‑old female with a disseminated tumor was reported six years aftersurgical treatment. In October 1993 the diagnosis of a bronchial carcinoid tumor was made and a left pneumonectomy was performed. No adjuvant treatment was indicated. In May 1999 a relapse was confirmed by cytology, and a treatment with rec‑hIFNa(10 MU intramuscular, thrice/week) was indicated. Her clinical condition improved, (ECOG 2 to 0), after three months of stable disease at evaluation, up to March 2002 when she developed a progressive disease as documented by abdominal CT scan. The histological block of the primary tumor was sent to the Centre of Molecular Immunologyin order to evaluate the recognition of the ganglioside molecule on the tumor by immunohistochemistry, which was informed as positive. In April 2002 we decided to begin a compassionate treatment with the vaccine NGcGM3/VSSP Montanide ISA 51 in combination with rec‑hIFNa. Since then up to now (56 months after progression with rec‑hIFNa alone) the patient still has stable disease. In summary, we observed very encouraging results that could support further studies in this type of patients(AU)